Affinity-independent memory B cell origin of the early antibody-secreting cell response in naive individuals upon SARS-CoV-2 vaccination.

Memory B cells (MBCs) formed over the individual's lifetime constitute nearly half of the circulating B cell repertoire in humans. These pre-existing MBCs dominate recall responses to their cognate antigens, but how they respond to recognition of novel antigens is not well understood. Here, we tracked the origin and followed the differentiation paths of MBCs in the early anti-spike (S) response to mRNA vaccination in SARS-CoV-2-naive individuals on single-cell and monoclonal antibody levels. Pre-existing, highly mutated MBCs showed no signs of germinal center re-entry and rapidly developed into mature antibody-secreting cells (ASCs). By contrast, and despite similar levels of S reactivity, naive B cells showed strong signs of antibody affinity maturation before differentiating into MBCs and ASCs. Thus, pre-existing human MBCs differentiate into ASCs in response to novel antigens, but the quality of the humoral and cellular anti-S response improved through the clonal selection and affinity maturation of naive precursors.

Li Z ，Obraztsova A ，Shang F ，Oludada OE ，Malapit J ，Busch K ，van Straaten M ，Stebbins E ，Murugan R ，Wardemann H ... -  《-》

Effect of timing of casirivimab and imdevimab administration relative to mRNA-1273 COVID-19 vaccination on vaccine-induced SARS-CoV-2 neutralising antibody responses: a prospective, open-label, phase 2, randomised controlled trial.

Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes. This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA. Participants were randomly assigned (per prespecified randomisation ratios within enrolment waves) according to a computer-generated randomisation scheme, stratified by age (<65 years and ≥65 years), to various intravenous or subcutaneous doses of casirivimab and imdevimab before, after, or at the same time as mRNA-1273 or to mRNA-1273 only. The doses of casirivimab and imdevimab were chosen to mimic various time intervals between receipt of 1200 mg of the mAb and the first dose of a primary series with mRNA-1273. The primary endpoint was vaccine-induced 50% inhibitory dilution neutralising antibody titres to SARS-CoV-2 spike protein, 56 days after the first vaccination. Secondary endpoints included vaccine-induced total antibodies to SARS-CoV-2 antigens and incidence of treatment-emergent adverse events. Exploratory endpoints included blood-derived T-cell and B-cell responses. The per-protocol set was used for the analysis of the primary endpoint and included all randomly assigned participants who received both doses of the vaccine and completed the injection or infusion of casirivimab and imdevimab per protocol, had no evidence of SARS-CoV-2 infection in the past or in the 56 days after the first dose of vaccine, and did not receive any intervention outside of the study that could alter the immune response. Safety was assessed in the safety analysis set, which included all randomly assigned participants who had received one or more doses of mRNA-1273 or any study drug, and analysed based on treatment received. The study is registered with ClinicalTrials.gov, NCT04852978, and is complete. Between April 29, 2021, and Nov 21, 2022, 807 participants were assessed for eligibility and 295 were randomly assigned. 293 participants were included in the safety analysis set and 260 were included in the per-protocol set. All vaccinated participants developed neutralising antibodies to SARS-CoV-2, with median titres above the published protective threshold (100 IU/mL) against the SARS-CoV-2 D614G variant (considered a reference strain at the time the initial COVID-19 vaccines were developed). Titres were decreased up to 4-fold (median titres 280-450 IU/mL for casirivimab and imdevimab vs 1160 IU/mL for vaccine only on day 56) when casirivimab and imdevimab was given 85 days or less before vaccination (150-1200 mg intravenously) or co-administered subcutaneously (600 mg or 1200 mg) with vaccination. Minimal reduction in neutralisation titres was observed in the 48 mg and 12 mg intravenous groups, corresponding to receipt of casirivimab and imdevimab 113 days and 169 days, respectively, before vaccination, and when administering the vaccine 6 days before the mAb. Across all groups, mAbs had a minimal effect on vaccine-induced total antibodies and T-cell responses to the spike protein. Casirivimab and imdevimab plus mRNA-1273 was generally well tolerated; a slight increase in treatment-emergent adverse events was observed in the casirivimab and imdevimab plus vaccine groups versus the vaccine-only group. Casirivimab and imdevimab administration before or at the time of COVID-19 vaccination reduced the elicitation of SARS-CoV-2 neutralising antibodies, but minimal effect was observed when vaccination occurred before mAb administration. Although the clinical significance of this decrease in neutralisation is unclear, this evidence suggests that further investigation of potential interactions could be warranted before concurrent clinical use of mAbs and vaccines targeting the same viral proteins as their main modes of action for the prevention or treatment of infectious diseases. Regeneron Pharmaceuticals and F Hoffmann-La Roche.

Isa F ，Gonzalez Ortiz AM ，Meyer J ，Hamilton JD ，Olenchock BA ，Brackin T ，Ganguly S ，Forleo-Neto E ，Faria L ，Heirman I ，Marovich M ，Hutter J ，Polakowski L ，Irvin SC ，Thakur M ，Hooper AT ，Baum A ，Petro CD ，Fakih FA ，McElrath MJ ，De Rosa SC ，Cohen KW ，Williams LD ，Hellman CA ，Odeh AJ ，Patel AH ，Tomaras GD ，Geba GP ，Kyratsous CA ，Musser B ，Yancopoulos GD ，Herman GA ，Trial Working Group ... -  《-》

SARS-CoV-2 variants of concern partially escape humoral but not T-cell responses in COVID-19 convalescent donors and vaccinees.

The emergence of SARS-CoV-2 variants harboring mutations in the spike (S) protein has raised concern about potential immune escape. Here, we studied humoral and cellular immune responses to wild type SARS-CoV-2 and the B.1.1.7 and B.1.351 variants of concern in a cohort of 121 BNT162b2 mRNA-vaccinated health care workers (HCW). Twenty-three HCW recovered from mild COVID-19 disease and exhibited a recall response with high levels of SARS-CoV-2-specific functional antibodies and virus-specific T cells after a single vaccination. Specific immune responses were also detected in seronegative HCW after one vaccination, but a second dose was required to reach high levels of functional antibodies and cellular immune responses in all individuals. Vaccination-induced antibodies cross-neutralized the variants B.1.1.7 and B.1.351, but the neutralizing capacity and Fc-mediated functionality against B.1.351 was consistently 2- to 4-fold lower than to the homologous virus. In addition, peripheral blood mononuclear cells were stimulated with peptide pools spanning the mutated S regions of B.1.1.7 and B.1.351 to detect cross-reactivity of SARS-CoV-2-specific T cells with variants. Importantly, we observed no differences in CD4+ T-cell activation in response to variant antigens, indicating that the B.1.1.7 and B.1.351 S proteins do not escape T-cell-mediated immunity elicited by the wild type S protein. In conclusion, this study shows that some variants can partially escape humoral immunity induced by SARS-CoV-2 infection or BNT162b2 vaccination, but S-specific CD4+ T-cell activation is not affected by the mutations in the B.1.1.7 and B.1.351 variants.

Geers D ，Shamier MC ，Bogers S ，den Hartog G ，Gommers L ，Nieuwkoop NN ，Schmitz KS ，Rijsbergen LC ，van Osch JAT ，Dijkhuizen E ，Smits G ，Comvalius A ，van Mourik D ，Caniels TG ，van Gils MJ ，Sanders RW ，Oude Munnink BB ，Molenkamp R ，de Jager HJ ，Haagmans BL ，de Swart RL ，Koopmans MPG ，van Binnendijk RS ，de Vries RD ，GeurtsvanKessel CH ... -  《Science Immunology》

Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1.

The continuous evolution of SARS-CoV-2, particularly the emergence of the BA.2.86/JN.1 lineage replacing XBB, necessitates re-evaluation of vaccine compositions1-3. Here, we provide a comprehensive analysis of the humoral immune response to XBB and JN.1 human exposure. We demonstrate the antigenic distinctiveness of XBB and JN.1 lineages in SARS-CoV-2-naive individuals and show that infection with JN.1 elicits superior plasma neutralization against its subvariants. We highlight the strong immune evasion and receptor-binding capability of KP.3, supporting its foreseeable prevalence. Extensive analysis of the B cell receptor repertoire, in which we isolate approximately 2,000 receptor-binding-domain-specific antibodies, with targeting epitopes characterized by deep mutational scanning, underscores the superiority of JN.1-elicited memory B cells4,5. Class 1 IGHV3-53/3-66-derived neutralizing antibodies (NAbs) are important contributors to the wild-type reactivity of NAbs against JN.1. However, KP.2 and KP.3 evade a substantial subset of these antibodies, even those induced by JN.1, supporting a need for booster updates. JN.1-induced Omicron-specific antibodies also demonstrate high potency across Omicron. Escape hotspots for these NAbs have already been mutated, resulting in a higher immune barrier to escape and indicating probable recovery of escaped NAbs. In addition, the prevalence of IGHV3-53/3-66-derived antibodies and their ability to compete with all Omicron-specific NAbs suggests that they have an inhibitory effect on the activation of Omicron-specific naive B cells, potentially explaining the heavy immune imprinting in mRNA-vaccinated individuals6-8. These findings delineate the evolving antibody response to the antigenic shift of Omicron from XBB to JN.1 and highlight the importance of developing the JN.1 lineage, especially KP.2- and KP.3-based vaccine boosters.

Jian F ，Wang J ，Yisimayi A ，Song W ，Xu Y ，Chen X ，Niu X ，Yang S ，Yu Y ，Wang P ，Sun H ，Yu L ，Wang J ，Wang Y ，An R ，Wang W ，Ma M ，Xiao T ，Gu Q ，Shao F ，Wang Y ，Shen Z ，Jin R ，Cao Y ... -  《-》

Cellular and humoral immunogenicity against SARS-CoV-2 vaccination or infection is associated with the memory phenotype of T- and B-lymphocytes in adult allogeneic hematopoietic cell transplant recipients.

We conducted a cross-sectional study to evaluate cellular and humoral immunogenicity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination or infection and examine how lymphocyte subpopulations in peripheral blood correlate with cellular and humoral immunogenicity in adult allogeneic hematopoietic cell transplantation (HCT) recipients. The median period from SARS-CoV-2 vaccination or infection to sample collection was 110.5 days (range, 6-345 days). The median SARS-CoV-2 spike-specific antibody level was 1761 binding antibody units (BAU)/ml (range, 0 to > 11,360 BAU/ml). Enzyme-linked immunosorbent spot (ELISpot) assay of T cells stimulated with SARS-CoV-2 spike antigens showed that interferon-gamma (IFN-γ)-, interleukin-2 (IL-2)-, and IFN-γ + IL-2-producing T cells were present in 68.9%, 62.0%, and 56.8% of patients, respectively. The antibody level was significantly correlated with frequency of IL-2-producing T cells (P = 0.001) and IFN-γ + IL-2-producing T cells (P = 0.006) but not IFN-γ-producing T cells (P = 0.970). Absolute counts of CD8+ and CD4+ central memory T cells were higher in both IL-2- and IFN-γ + IL-2-producing cellular responders compared with non-responders. These data suggest that cellular and humoral immunogenicity against SARS-CoV-2 vaccination or infection is associated with the memory phenotype of T cells and B cells in adult allogeneic HCT recipients.

Konuma T ，Hamatani-Asakura M ，Nagai E ，Adachi E ，Kato S ，Isobe M ，Monna-Oiwa M ，Takahashi S ，Yotsuyanagi H ，Nannya Y ... -  《-》